Perhydro-1,2,4-thiadiazinedioxides-(1,1) and their preparation



United States Patent 3,423,408 PERHYDRO-1,2,4-THIADIAZINEDIOXIDES-(1,1)AND THEIR PREPARATION Rolf Wilhelm Pfirrmann, Lucerne, Switzerland,assignor to Ed. Geistlich Sohne AG fur Chemische Industrie,

Lucerne, Switzerland, a Swiss body corporate No Drawing. Filed Oct. 4,1965, Ser. No. 492,930 Claims priority, application Great Britain, Oct.6, 1964,

40,734/ 64 US. Cl. 260243 17 Claims Int. Cl. C0711 93/22, 93/32 ABSTRACTOF THE DISCLOSURE There are provided novelperhydro-1,2,4-thiadiazinedioxides of the formula I Cfiz \S O: Iii-I 1(IJHZ Cfig (where R and R which may be the same or different arehydrogen atoms, alkyl groups having 1-8 carbon atoms, cycloalkyl group,aralkyl groups, aryl groups or heterocyclic groups or together with theperhydrothiadiazinedioxide ring to which they are attached form a ringof perhydrothiadiazinedioxide nuclei separated by methylene groupsjoining nitrogen atoms of adjacent nuclei) and their physiologicallyacceptable acid addition salts. The new compounds are prepared byreacting a taurineamide of the formula R NH-CH -CH SO NH-R withformaldehyde or a substance liberating formaldehyde, and they showstrong bactericidal activity against both gram negative and grampositive bacteria and against fungi.

This invention relates to novel compounds having bactericidal andfungicidal activity and to a process for their preparation.

According to the present invention, there are providedperhydro-1,2,4-thia diazinedioxides-(1,1) of the general formula "iceagainst both gram negative and gram positive bacteria and against fungi.

They are also active against many strains resistant to antibiotics suchas penicillin. The toxicity of the compounds is very low and, forexample, the product of Example 4 hereinafter has an LD per os in whitemice of 2000-2500 mg./ kg. as well as excellent activity against Staph.aur haem. 1, Strept. pyog. haem. 6293, Entrococcen 3, S. paratyphi-B 5,S. typhi 6, B. proteus vulg. 8, Pseudomonas aeruginosa 7, Shig. sonnel12 b, E. coli 5494 and B. mesenterious, as well as Candida albicans,Aspergillus niger, T richophyton gypseum and Epidermoph. interdigitale.

The substituents R and R may carry substituents, for example, halogenatoms or hydroxy, amino, acylamido, carboxy, esterified carboxy, alkoxyor nitro groups and, in particular, one or both of R and R may be amethylene group linked to the nitrogen atom in the 2- or 4-position of aperhydro-1,2,4-thiadiazinedioxide-(1,1) ring carrying a substituent R atthe remaining nitrogen atom, where R has the above meaning includinghydrogen.

It will thus be seen that the invention includes such compounds as WhereR has the above meaning.

In general, compounds of general Formula II are referred for theiruseful physiological activity and low toxicity.

The acid addition salts according to the invention include, for example,the hydrohalides, sulphates, phosphates, nitrates, acetates, citrates,tartrates, maleates or succinates. Those substances in which R ishydrogen tend to form betaines which do not themselves form stable acidaddition salts.

The substituents R and R can thus, besides the above heterocyclicgroups, also, for example, be methyl, ethyl, chloroethyl, hydroxyethyl,aminoethyl, carbethoxymethyl, propyl, isopropyl, butyl, isobutyl,l-methylpropyl, tertiary butyl, hexyl, cyclohexyl, methylcyclohexyl,benzyl, phenyl, chlorophenyl, :methoxyphenyl, chloronitrophenyl ordimethylnitrophenyl groups.

Particularly preferred compounds having regard to their bactericidalactivity are that of Formula II in which R is hydrogen or those ofFormula I in which R and R are both cyclohexyl, both n-butyl, or are aphenyl group and n-butyl group respectively. It is preferred that atleast one of the groups R and R is hydrogen or an alkyl, cycloalkyl,aryl or heterocyclic group.

According to a further feature of the present invention there areprovided pharmaceutical compositions comprising one or more compounds ofFormula I in which R and R have the above meanings together with one ormore pharmaceutical carriers or excipients.

Thus, for example, the compositions may take the form of tablets,dragees, capsules, lozenges, suppositories, ampoules for injection,syrups, linctuses, ointments, lotions, pastes, solutions, aerosol spraysetc.

The carriers or excipients in such compositions may, for example, bethose conventional for such forms and may include starch, lactose,magnesium stearate, talc, gelatin, sterile water, suspending,emulsifying, dispersing, thickening or fiavouring agents, ointment basesor aerosol propellants.

Dosage units forms such as tablets, capsules, suppositories or ampoulesare preferred and advantageously each unit contains to 1000 mg. ofactive substances, preferably 100 to 200 mg.

In the case of the product of Formula II in which R is hydrogen, aparticularly active substance, topical formulations are preferred, forexample, powders, ointments, spray, solutions etc.

The compositions, and particularly the non-dosage forms such as syrups,ointments etc. preferably contain the active substance at aconcentration between 0.10 and 20.0% by weight, preferably between 0.5and 2.0% for aqueous solutions or aerosol sprays or up to 10% forpowders and ointments.

The new compounds according to the invention may be prepared in anyconvenient way. According to a still further feature of the invention weprovide a process for the production of compounds of general Formula Iin which R and R have the above meanings in which a taurineamide of thegeneral formula or an acid addition salt thereof is subjected to ringclosure for example by reaction with formaldehyde or a substanceliberating formaldehyde.

The reaction is preferably effected in an inert solvent medium, forexample water or an organic solvent such as a substituted amide, e.g.,dimethylformamide or dimethylacetamide, an ester, e.g., tetrahydrofuran,dioxan or diethyl ether, a hydrocarbon or nitro-hydrocarbon, e.g.,benzene or nitrobenzene, an alkanol, e.g., methanol or ethanol or ahalogenated hydrocarbon e.g., chloroform or dichloroethane. Theformaldehyde is preferably reacted in aqueous solution but aformaldehyde releasing compound such as paraformaldehyde, for example insolution in an organic solvent, if desired in admixture with Water, mayalso be used.

The reaction conditions will vary with the nature of the reactants, forexample, Whether R and R are aliphatic or aromatic,.but the reactiontemperature will in general be between and 120 C. The pH of the reactionmixture is advantageously weakly alkaline, e.g., pH 8.0 and may ifdesired be adjusted, e.g., with bicarbonate.

The ratio of formaldehyde to the taurineamide starting compound ispreferably 1:1 or greater, Where one of the substituents R and R ishydrogen, however, reaction at the cyclic NH groups is possible to formmethylene bridges linking two thiadiazine dioxide rings as in compoundsof Formula II while when both R and R are hydrogen, compounds of FormulaIII may be formed. Where compounds of Formula II are required, the ratioof formaldehyde to taurineamide is preferably at least 3:2 and whencompounds of Formula III are required the ratio is preferably at least2: 1.

The reaction time is preferably in the range of 20 to 200 minutes,preferably about minutes.

It is also possible to convert compounds of Formula II into mono-nuclearcompounds of Formula I by catalytic hydrogenation, for example using aplatinum oxide catalyst at normal pressures of hydrogen.

The taurineamides used as starting material in the process of theinvention may be prepared by reacting ammonia or primary amines withvinyl sulphonamides of the general formula CH =CHSO -NHR where R has themeaning given above. The taurineamide may also be prepared by reactingtaurine with phthalic anhydride to give the phthalimido derivative whichmay then be converted into an amide via the acid halide followed byremoval of the phthalyl group in the usual way.

In order that the invention may be well understood, the followingexamples are given by Way of illustration only:

Example 1 4-n-butyl-Z-phenyl-perhydro-1,2,4-thiadiazinedioxide (1,1), CH O N S/268J3. M.P.: 5863 C.

Analysis. Calculated: C, 58.19%; H, 7.51%; N, 10.44%. Found: C, 58.48%;H, 7.28%; N, 10.37%.

15.0 g. of n-butyl-fi-amino-ethyl-sulphonyl-aniline were dissolved inml. of 96% alcohol and boiled with 20 ml. of 40% formaldehyde underreflux; water was then added to complete cloudiness. The reactionmixture was evaporated in vacuo to dryness, the residue taken up withether, washed with water and the ethereal solution dried and distilledoff.

15 g. of oil were obtained as a residue which crystallised frompetroleum ether on standing. Recrystallised from 400 ml. of hexane: 8.0g. of desired product as pure white crystals of M.P. 57-63 C.

Recrystallised from hexane for analysis. Then-butylamino-ethyl-sulphonyl-aniline used as starting material may beprepared from vinyl-sulphonyl-aniline by addition of n-butylamine.

Example 2 2,4-dicyclohexyl-perhydro 1,2,4 thiadiazine-dioxide- (1,1), CH O N S/30039. M.P.: l00-l02 C.

Analysis.--Calculated: C, 59.97%: H. 9.40%; N, 9.33%. Found: C, 59.80%;H, 9.32%; N, 9.37%.

1.1 g. of the compound were dissolved in 30 ml. of H 0 and 40 ml. of 95%alcohol; 5 ml. of 40% formaldehyde were added, the pH was adjusted with(a little) NaHCO to 8 and the solution was :boiled for half an hourunder reflux. The slightly cloudy solution was colled and theprecipitate filtered with suction. 800 mg. of the desired product aswhite crystals of M.P. 99101 C. were obtained.

Recrystallised from alcohol for analysis.

Example 3 2,4-di-n-butyl perhydro 1,2,4 triadiazinedioxide- (1,1); C H ON S/24832; collected at /0.1 mm.

Arzalysis.Calculated: C, 53.20%; H, 9.47%; N, 11.28%. Found: C, 53.20%;H, 9.70%; N, 11.34%.

8.0 g. of n butyl-B-amino-ethyl-sulphonyl butylamine were boiled for 30minutes under reflux with 10 g. of 40% formaldehyde in 50 ml. of waterand 0.5 g. of NaHCO The solution was then etherified at pH 7 and theether washed with water, dried and distilled off.

7.7 g. of the desired product as a yellow clear oil were obtained asresidue which boiled at high vacuum (140 C./0.1 mm.). Distilled at highvacuum: 1.6 g. of a slightly yellow oil (residue of starting material);

B.P. 134 C./0.4 mm.; collected for analysis,

Example 4 C7H16N404S21 MOI-i M.P.: 154-158 C.

Analysis.Caloulated: C, 29.55%; H, 5.67%; N, 19.70%. Found: C, 29.99%;H, 6.31%; N, 19.92%.

3.2 g. of taurinamide hydrochloride were dissolved in ml. of water and 2g. of NaHCO added. 2 g. of 38% formaldehyde was added dropwise and thereaction mixture then all-owed to stand.

The precipitate was filtered with suction and the reaction productcrystallised slowly. Yield: 1.9 g. of the desired product as whitecrystals of M.P. 154-158 C.

C H N S O molecular weight: 592.76; M.P.: 210 215 C.

Analysis-Calculated: C, 32.43%; H, 5.44%; N, 18.91%. Found: C, 32.42%;H, 5.89%; N, 18.31%.

8 g. of taurinamide hydrochloride were dissolved in 50 ml. of water and7.5 g. of NaHCO added. 8.75 g. of 40% formaldehyde were added slowly anddropwise to the reaction mixture which was allowed to stand for 48hours. The crystalline precipitate was filtered with suction; 8.7 g.were obtained which were 'boiled with 700 ml. of acetone. The insolublecomponents were filtered off and recrystallised from a little water.

A substance according to Example 4 of M.P. 154158 C. was found in theacetone mother liquor.

Example 6 sH1 (.3aH7

Example 7 \SO2 CH2 C H N O S /396A4; M.P.: 103-106 C.

6 Analysis-Calculated: C, 45.43%; H, 8.14%; N, 14.13%. Found: c, 45.41%;H, 8.15%; N, 14.08%.

11 g. of the compound were dissolved in 50 ml. of water and neutralisedwith 5 g. of NaHCO 15 ml. of 38% formaldehyde were added to the clearsolution which was then allowed to stand for several hours. Theprecipitated reaction product was filtered with suction andrecrystallised from absolute alcohol. 5 g. of desired product of M.P.103106 C. were obtained.

Example 8 -Q- 1 a W-CW CH2 CH2 CH2 CH2 NCHr-N C H O N S Cl 502.44; M.P.:195-196 C.

Analysis.Calcu1ated: C, 45.40%; H, 4.41%; N, 11.75%. Found: C, 45.65%;H, 4.58%; N, 11.61%.

2.34 g. of the compound were dissolved in ml. of hot water, heated underreflux for 30 minutes together with 9 ml. of 40% formaldehyde andevaporated in vacuo to dryness.

The residue dissolved in CHClg, was dried over sodium sulphate and againevaporated. The residue was dissolved in 100 ml. of hot water andfiltered with suction, recrystallised from alcohol; yield: 2 g. ofdesired product of M.P. 196 C.

Example 9 C H N O SCl/302819; M.P.: 6970 C.

Analysis.-Calcul-ated: C, 51.56%; H, 6.32%; N 9.25%. Found: C, 58.86%;H, 5.74%; N, 9.32%.

17 g. of the compound were dissolved in 100 ml. of alcohol and heatedunder reflux for 30 minutes together with 15 ml. of 30% formaldehyde.

9.70%. Found: C, 49.83%; H, 6.04%; N, 9.81%.

15 g. of the compound were dissolved in 100 ml. of alcohol and, togetherwith 13 ml. of 30% formaldehyde, heated under reflux for 45 minutes.Thereaction solution was evaporated to dryness,

7 distributed between ether and water and the ethereal phase dried overNa SO and evaporated.

The residue was crystallised from alcohol and recrystallised fromalcohol. Yielded 12 g. of the desired product of M.P. 7l72 C.

Example 11 CH; l z

ofia C H O N S/30232; M.P.: 103105 C.

Analysis.Calculated: C, 63.56%; H, 6.00%; N,

9.27%. Found; C, 63.02%; H, 5.80%; N, 9.07%.

10.0 g. of the compound were dissolved in 100 ml. of 96% alcohol andboiled with 15 ml. of 40% formaldehyde for three hours under reflux.Water was added to complete cloudiness and then decanted; theprecipitated oil was taken up with ether, dried and distilled off.

8.4 g. of a brown oil was dissolved in alcohol, cooled and filtered withsuction. 4 g. of the desired product as white crystals of M.P. 98103 C.were obtained which were recrystallised from alcohol for the analysis.

Example 12 Cllf CH, CH: lHg

NCH CH C11H 5N2O2SCl/274.77; M.P.: 72-'73 C.

Analysis.Calculated: C, 48.09%; H, 5.50%; N, 10.20%. Found: C, 48.15%;H, 5.54%; N, 10.12%.

12 g. of the compound HCl were dissolved in 100 ml. of alcohol and 1.6g. of NaOH dissolved in about 5 ml. of water added. Then ml. of 40%formaldehyde were added to the reaction solution which was heated for 1%hours under reflux.

It was then evaporated to dryness in vacuo and taken up with CHCl/water. The chloroform was dried and distilled oil and the oilcrystallised slowly. The residue 7 was triturated with petroleum ether,filtered with suction and recrystallised from alcohol/petroleum ether. 7g. of the desired product as crystals of M.P. 72-73" C. were obtained.

Example 13 S02 C1 N CH. (I111; CH2

C H N O SCl/260.741; M.P.: 92-93 C.

Analysis.Calculated: C, 46.06%; H, 5.02%; N, 10.75%. Found: C, 46.21%;H, 5.03%; N, 10.65%.

11.4 g. of the compound HCl were dissolved in 100 ml. of alcohol and 1.6g. of NaOH dissolved in about 5 ml. of water added. The precipitate wasfiltered with suction and 10 ml. of 40% formaldehyde added to the clearsolution, which was heated for 1 hour under reflux and then evaporatedto dryness. The oily residue was taken up with chloroform and water, thechloroform dried, filtered and distilled off. 8.5 g. of crystals of thedesired product were obtained which were recrystallised fromalcohol/petroleum ether.

Example 14 CHz-CH N I CzHs CH1 \CH1 6H. 1l

Analysis.-Calculatedz C, 57.86%; H, 8.09%; N, 13.50%. Found: C, 57.95%;H, 8.06%, N. 13.47%.

10 g. of

CH1 CH C H N O S/29434; M.P.: 131-133 c.

Analysis-Calculated: C, 61.20%; H, 7.53%; N, 9.52%. Found: C, 60.64%; H,8.03; N, 9.54%.

14.0 g. of the compound were dissolved in 50 ml. of alcohol and 15 ml.of 30% formaldehyde added. The solution was heated with stirring for onehour under reflux, ml. of water then added and a white product obtained.The product was filtered with suction, washed with water and dried. 14g. of the desired product as a white crystallised product of M.P.131-133" C. were obtained.

Example 16 emu-11K Us: S02 C 2 Analysis.Calculated: C, 59.55%; H. 7.85%;N, 9.92%. Found: C, 59.61%; H, 7.80%; N, 9.92%.

14.5 g. of N-n-amyl-fi-amino-ethyl sulphonyl aniline in ml. of alcoholwere heated with 20 g. of 40% formaldehyde for two hours under reflux.The reaction solution was concentrated in vacuo, the residue taken upwith ether, washed with water, dried and distilled otf.

21.0 g. of the compound are dissolved completely in 100 ml. water and100 ml. ethanol (96%) containing 9 g. NaHCO 2.0 g. formaldehyde (40%)are added and the solution is allowed to stand for 2 days at roomtemperature. The precipitated large, white crystals are then filteredwith suction to yield 8.1 g. of white crystals of M.P. 75-80 andcrystallised for analysis from ether/petroleum ether to give 5.7 g. ofwhite crystals of M.P. 77-79".

Analysis.-Calculated: C, 52.39%; M, 6.09%; N 9.42%. Found: C, 52.36%; M,6.09%; N, 9.48%.

The taurinamide starting compound (M.P. 190-195 C.) is a new compoundwhich may be prepared by the method of Goldberg (J.C.S. 1945, pp.464-467).

Example 18 (a) NH C4Ht0N2 t CH: X0; M01=150.2

CH -N CH;

g. turinamide hydrochloride were dissolved in 50 ml. anhydrous formicacid, 6.1 g. formaldehyde (40%) were added and the mixture heated for 1hour under reflux. The contents of the flask were then evaporated todryness using a rotational evaporator to yield an oil which crystallisedon addition of alcohol, giving 2.4 g. of white crystals. These weredissolved in a little water, neu-tralised with NaHCO and the baseextracted by shaking with methylene chloride, removal of solvent anddrying in vacuo. The residue was recrystallised from alcohol. Yield: 0.7g. white crystals, M.P. 138.5-l39.3 C.

Analysis.-Calculated: C, 31.99%; H, 6.71%; N, 18.66%. Found: C, 32.16%;H, 6.85%; N, 18.59%.

' no depression. The IR-spectra, taken in methylene chloride, showed nodifferences in absorption between'3 and 15,14.

Example 19' Spray composition: Percent Product of Example 4 (5 grainsize) 2 Mixture of fatty acid esters, for example isopro- 10 Spraycomposition: Percent pylrnyristate, purcelline oil etc. 5 Perfume oil0.5

Rest add 100 g. monofluoro-dichloromethane and difluorodichloromethane(50/50) or difluorodichloromethane alone.

The composition is filled into aerosol spray containers under pressure.

Example 20 Ointment: Grams Product of Example 4 100 Wool fat White softparafiin 900 The fat and parafiin are melted, mixed together and cooled.The active compound is then blended in.

The powders are blended and damped with starch paste followed bygranulation. After drying the granules are blended with magnesiumstearate and compressed into tablets each containing 50 mg. activecompound.

Example 22 Powder: Grams Product of Example 4 10 Starch 10 Purifiedtalc, up to grams. I claim:

1. A perhydro-1,2,4-thiadiazinedioxide-(1,1) of the formula 1 CH: 30, RN\ /GH where R and R, which may be the same or different, are hydrogenatoms, alkyl groups having l-8 carbon atoms, cyclohexyl, monocarbocyclicaralkyl groups having l-8 carbon atoms in the alkyl portion, phenyl or al,l-dioxido-perhydro-1,2,4-thiadiazinylmethyl group or together with theperhydrothiadiazinedioxide ring to which they are attached form a ringof perhydrothiadiazinedioxide nuclei separated by methylene groupsjoining nitrogen atoms of adjacent nuclei and their physiologicallyacceptable acid addition salts.

2. A compound as claimed in claim 1 having the formula R1 1 25'; (3H2(13H:

N H2 CH: cfil where R has the meaning given in claim 1 and and itsphysiologically acceptable acid addition salts.

3. A compound as claimed in claim 1 in which one or both of R and Rcarry halogen atoms or hydroxy, amino, carboxylic acylamido, carboxy,carbalkoxy having l-8 carbon atoms in the alkyl portion, alkoxy having1-8 carbon atoms in the alkyl portion, methyl or nitro groups assnbstituents.

4. A compound as claimed in claim 1 in which one or both of R and R is amethyl, ethyl, chloroethyl, hydroxyethyl, aminoethyl, carboxymethyl,propyl, isopropyl. butyl, isobutyl, l-methylpropyl, tertiary butyl,hexyl, cyclohexyl, methylcyclohexyl or benzyl group.

5. A compound as claimed in claim 2 in which R is hydrogen and itsphysiologically acceptable acid addition salts.

6. A compound as claimed in claim 1 in which the acid addition salts arethe hydrohalides sulphates, phosphates, nitrates, acetates, citrates,tartrates, maleates or succinates.

7. A process for the production of a compound as claimed in claim 1 inwhich a taurineamide of the formula is reacted with formaldehyde or asubstance liberating formaldehyde.

8. A process as claimed in claim 7 in which the reaction is effected inan inert solvent medium.

9. A process as claimed in claim 8 in which the solvent is water, asubstituted amide solvent, a cyclic or acyclic ether solvent, ahydrocarbon or nitro-hydrocarbon solvent, an alkanol solvent or ahalogenated hydrocarbon solvent.

10. A process as claimed in claim 7 in which the formaldehyde liberatingsubstance is paraformaldehyde.

11. A process as claimed in claim 7 in which the reaction temperature is20120 C.

12. A process as claimed in claim 7 in which the reaction medium isweakly alkaline.

13. A process as claimed in claim 7 in which the ratio of formaldehydeto taurinamide is at least 1:1.

14. A process as claimed in claim 7 in which a compound as defined inclaim 2 is produced and is converted into the compound of claim 1 inwhich R and R are hydrogen by catalytic hydrogenation.

15. A process as claimed in claim 14 in which hydrogenation is elfectedusing platinum oxide as catalyst.

16. A process as claimed in claim 7 in which the taurinamide startingmaterial is prepared by reacting ammonia or a primary amine R NH with avinyl sulphonamide of the formula CH =CHSO NHR R and R having themeanings given in claim 1.

17. A process as claimed in claim 7 in which the taurinamide startingmaterial is prepared by reacting the phthalimido derivative of an acidhalide of taurine with a primary amine followed by removal of thephthalyl group.

References Cited UNITED STATES PATENTS 2,466,396 4/1949 Dickey 260-2433,103,511 9/1963 Bernstein et al. 260-243 3,108,124 10/1963 Close 260243HENRY R. JILES, Pirmary Examiner.

JOHN M. FORD, Assistant Examiner.

U.S. Cl. X.R.

